The present invention provides novel methods in designing synthetic antibiotic analogs with enhanced antimicrobial and therapeutic properties. One of many particularly interesting groups of antimicrobials that could benefit from the proposed modifications is called lantibiotics.
The present invention in a preferred embodiment utilizes natural lantibiotic products, synthetic lantibiotic products, or mutagenized lantibiotic products for the subsequent chemical addition of a thiol compound carrying a novel functional group and includes antimicrobial compounds containing an alpha beta unsaturated carbonyl group labeled with a thiol compound.
Lantibiotics are antimicrobial peptides that have potential usefulness in treating infectious diseases. They are known to have a potent and broad spectrum of activity, an insignificant cytotoxicity, and demonstrated efficacy in animal infection models, suggesting therapeutic potential.
The present invention provides a novel and distinctive technology called functional enhancement of antimicrobials (FEAM) that provides novel methods for the manufacture of novel lantibiotic analogs with enhanced functions and novel antimicrobial compounds that have enhanced properties. Enhancement of the antimicrobial compounds refers to improvements in the physical and chemical (physicochemical) properties. The premise for this technology involves understanding that defined and undefined constraints on lantibiotics prevent nature from making the most effective bactericidal compound. A single addition of a functional group, such as a charge group, polar group, or a hydrophobic group can have significant effects on the bioactivities, pharmacokinetics, and/or pharmacodynamics of an antimicrobial compound. As described herein, 2,3-didehydroalanine (Dha) and 2,3 didehydrobutyrine (Dhb) residues are commonly found in lantibiotics, as well as other ribosomally and non-ribosomally synthesized antimicrobials. The present invention makes use of the alpha, beta unsaturated carbonyl group found in these residues, which lend themselves to the addition of thiol compounds containing novel functional groups in a highly selective fashion. The single step additions are easily optimized and can be made in aqueous solvents with greater than a 90% yield. Furthermore, Dha and Dhb residues are easily engineered in lantibiotics by site directed mutagenesis or by an organosynthesis method, further facilitating the production of unique analogs with enhanced functions. The invention provides for the creation of novel lantibiotic analogs that contain a reactive carboxyl group or amino group which facilitates the addition of other functional groups using standard coupling chemistry.
A need exists in the field of antibiotics, and specifically lantibiotics, for a method of enhancing the pharmacokinetic and the pharmacodynamic activity of antimicrobial compounds. The present invention provides such a method.